Neural stem cell lineage-specific cannabinoid type-1 receptor regulates neurogenesis and plasticity in the adult mouse hippocampus

Abstract

Neural stem cells (NSCs) in the adult mouse hippocampus occur in a specific neurogenic niche, where a multitude of extracellular signaling molecules converges to regulate NSC proliferation as well as fate and functional integration. However, the underlying mechanisms how NSCs react to extrinsic signals and convert them to intracellular responses still remains elusive. NSCs contain a functional endocannabinoid system, including the cannabinoid type-1 receptor (CB1). To decipher whether CB1 regulates adult neurogenesis directly or indirectly in vivo, we performed NSC-specific conditional inactivation of CB1 by using triple-transgenic mice. Here, we show that lack of CB1 in NSCs is sufficient to decrease proliferation of the stem cell pool, which consequently leads to a reduction in the number of newborn neurons. Furthermore, neuronal differentiation was compromised at the level of dendritic maturation pointing towards a postsynaptic role of CB1 in vivo. Deteriorated neurogenesis in NSC-specific CB1 knock-outs additionally resulted in reduced long-term potentiation in the hippocampal formation. The observed cellular and physiological alterations led to decreased short-term spatial memory and increased depression-like behavior. These results demonstrate that CB1 expressed in NSCs and their progeny controls neurogenesis in adult mice to regulate the NSC stem cell pool, dendritic morphology, activity-dependent plasticity, and behavior.

Poor Concordance of Floxed Sequence Recombination in Single Neural Stem Cells: Implications for Cell Autonomous Studies

“…Our findings do not necessarily undermine previous studies which have identified cell autonomous gene functions using stop-floxed reporters as a marker of target gene recombined cells (Zhou et al, 2018;Zimmermann et al, 2018;Franz et al, 2019;Zhang et al, 2019). Aside from the possibility that other reporter-target combinations show better recombination concordance than the two genes used in this study, if target gene recombination has a large cell-autonomous effect, it may still be detectable in models with suboptimal reporter-target recombination concordance due to the subpopulation of cells in which fluorescent protein presence is a true signal.…”

“…In many studies, NSPC-targeted CreER T2 -lox systems are combined with a ubiquitously-expressed stop-floxed fluorescent reporter gene to confirm recombination in NSPCs (Sun et al, 2014;Kirby et al, 2015;Tannenholz et al, 2016). It is also common to use these fluorescent proteins more cell-specifically to investigate cell autonomous effects of recombination in the experimental gene of interest (Zimmermann et al, 2018;Zhou et al, 2018;Franz et al, 2019;Zhang et al, 2019).…”

A Guide to Targeting the Endocannabinoid System in Drug Design

“…CB1, CB2, and GPR55 take part in the regulation of neurogenesis. CB1 and GPR55 are crucial for proliferation and differentiation of neural stem cells (NSCs) [162][163][164]. Additionally, CB1 and CB2 control the development of astrocytes [165].…”

Cannabinoid Type 1 Receptor is Undetectable in Rodent and Primate Cerebral Neural Stem Cells but Participates in Radial Neuronal Migration

“…Observed actions of cannabis and endocannabinoids on proliferating neurons [ 27 , 28 ] may be less direct and, for example, may be transmitted through other molecules, cells, organs or the maternal organism. Potential actions of CB 1 R in later prenatal and postnatal proliferation zones such as the neocortical outer SVZ or hippocampal dentate gyrus [ 42 ] demands further investigation using methods with high cellular and subcellular resolution.…”